Methods and apparatus for skin color patient monitoring

ABSTRACT

Methods and apparatus for diagnosing cardiovascular health in a patient by monitoring changes in skin redness levels, which is associated with perfusion and ability of circulatory system to adapt to physical exertion. Color detectors including colorimeters and spectrophotometers may be used to monitor and quantify skin color. Wet run solutions such as acetylcholine solutions may be applied to the skin area being monitored. Skin redness can be monitored during the course of exercise or a stress test, as well as during recovery. Wearable color detector devices can be worn by patients during exercise.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates generally to the field of health andmedicine, and in particular to a new and useful spectrophotometriccolorimeter methods and apparatus to measure and store the color of asubject's skin over time for tracking and diagnosing aspects of thesubject's cardiovascular condition.

In physiology, “perfusion” is the process of a body delivering blood tocapillary beds in living tissues. As more or less blood is delivered tocapillaries near a skin surface, the color of the skin changes. Forexample, skin having more blood delivered near the surface is more redthan skin on the same individual having less blood. Aspects of the workleading to this invention have determined that changes in skin color andperfusion will be greater for patients in better cardiovascular health,and smaller for patients who are not in good cardiovascular health, fora given stimulus.

Endothelium is a type of epithelium that lines the interior surface ofblood vessels and lymphatic vessels. It is a thin layer of simplesquamous cells called endothelial cells. Vascular endothelial cells linethe entire circulatory system, from the heart to the smallestcapillaries. Endothelium of the interior surfaces of the heart chambersis called endocardium. Endothelial dysfunction is linked to variousvascular diseases, and is often regarded as a key early event in thedevelopment of atherosclerosis. Impaired endothelial function, which cancause hypertension and thrombosis, is often seen in patients withcoronary artery disease, diabetes mellitus, hypertension,hypercholesterolemia, and in smokers. Endothelial dysfunction is alsocorrelated with future adverse cardiovascular events.

In blood vessels, vascular smooth muscle cells are behind theendothelial cells, the endothelial cells forming a thin layer betweenthe blood and the muscle cells. Vascular smooth muscle contracts orrelaxes to change both the diameter of blood vessels and, as a result,the local blood pressure. Arteries have more smooth muscle than veins,and so generally have greater thickness. Endothelial cells affect themovement of substances (such as nitric oxide) from the blood to thevascular smooth muscle cells which, in turn, dilate and contract thevessel. Proper functioning of the vascular endothelium and vascularsmooth muscle cells, together, is important for fast end effectivephysiological response to stresses such as exercise.

Nitric oxide is an important signaling molecule involved in variousphysiological and pathological processes. Of particular relevance here,nitric oxide is a powerful vasodilator which has a very short half-lifein the blood. Nitroglycerine and amyl nitrite, used to treat heartconditions, are precursors of nitric oxide.

The vascular endothelium could be considered the largest organ in thehuman body: the area inside the lungs alone can have a surface area ofover 3,500 square feet, larger than a tennis court. Oxygen, carbondioxide, and other important substances pass through the endothelium inthe lungs, blood vessels, and elsewhere, making it important inregulating homeostasis. Hormones and other vasoactive substances affectthe functioning of the endothelium. For example, the permeability of thevascular endothelium varies in response to oxygen levels, hormones, andother stimuli.

The endothelium has a variety of functions. Endothelium plays a role incontrolling vascular tone—i.e. the degree of constriction or dilation.This, in turn, affects blood pressure and blood flow. It is aphysiological barrier which regulates the flow of substances into andout of the vasculature. Some of these substances, in turn, affect vesselwall phenotype. Vascular endothelial cells also act as signaltransducers between the blood and other cells (e.g. smooth musclecells). Vascular endothelial cells are involved in fluid filtration andhormone trafficking. It is involved in the removal and biotransformationof many drugs. It participates in immune responses, such as by bindingimmune complexes and immunological blood components.

Alterations to endothelium has been found to be a precursor to otherconditions. For example, changes to the endothelium have been identifiedas precursors of diabetes linked atherosclerosis.

The endothelium is regulated by vasoactive compounds such as angiotensinII, prostacyclin, thromboxane A2, nitric oxide (NO), and endothelins. Itcan also produce and release vasoactive compounds. It is also effectedby the expression and activity of enzymes such as angiotensin convertingenzyme, endothelin converting enzyme, nucleotidases, NO synthase, andlipoprotein lipase. Disease states, in turn, can affect the ability ofthese mediators to control the vasculature normally.

Vasodilation is a term for the widening of blood vessels. Vasodilationresults from relaxation of smooth muscle cells in the vessel walls,particularly in the large veins, large arteries, and smaller arterioles.The opposite of vasodilation is vasoconstriction, i.e. the narrowing ofblood vessels. When blood vessels dilate, blood flow increases due to adecrease in vascular resistance. This also typically decreases bloodpressure. Vasodilation and vasoconstriction response may be intrinsic(due to local processes or stimuli) or extrinsic (due to circulatinghormones or the nervous system). In some cases vasodilation andconstriction are systemic—i.e. occurring simultaneously throughout thecirculatory system. Substances that cause vasodilation are calledvasodilators. Vascular dilation decreases endothelial “resistance” toblood flow by opening a wider passage for the blood. Constriction, inturn, increases resistance by narrowing the passage.

Dr. Robert Furchgott (1916-2009) was a Nobel Prize-winning Americanbiochemist who contributed to the identification of nitric oxide as atransient cellular signal in mammals. His publically available NobelPrize lecture publication outlines his work in this area and providesuseful background. Endothelium-Derived Relaxing Factor: Discovery, EarlyStudies, and Identification as Nitric Oxide, Robert F. Furchgott, Dec.8, 1998.

Aspects of the work leading to this invention have determined thatobservations of vascular endothelium in blood capillaries supplying theskin provide information regarding the vascular endothelium elsewhere,such as in the same individual's heart.

Reflected color can be measured using a spectrophotometer, whichtypically makes measurements in the visible light region of a givencolor sample. Spectrophotometry uses photometers that can measure alight beam's intensity as a function of its color or wavelength. If, forexample, readings are made at 10 nanometer increments, the visible lightrange of 400-700 nm will yield 31 readings. These readings can be usedto draw a reflectance curve illustrating how much light of eachwavelength is reflected, as a function of wavelength.

Colorimeters are an alternative to spectrophotometers. Colorimeterstypically make a limited number of wideband spectral energy readingsalong the visible spectrum by using filtered photodetectors.

The generic term “color detector” refers to spectrophotometers,colorimeters, and their functional equivalents which are capable ofdetecting and quantifying at least red wavelengths.

The Konica Minolta CM 700d spectrophotometer is a handheld unit that iscapable of accurately quantifying the color of a surface. It is a largeunit, however, that is not suitable to be worn like a wristwatch. U.S.Pat. No. 5,043,571, originally assigned to Minolta Camera KK, disclosesa color CCD based spectrophotometer that is amenable to miniaturization,however.

Colors can be defined numerically, and differences between two colorscan also be calculated and defined numerically. Several quantitativecolor systems exist, and can be adapted for use with this invention.

One available system is the L*a*b* color space or Hunter L/a/b colorspace, which can be visualized as a rectangular 3D coordinate system. Lindicates lightness, a is the red/green coordinate, and b is theyellow/blue coordinate. L can have a value from 0 (black) to 100(perfect reflection). The a and b axes have no numerical limits.Coordinate a is positive when red, and negative when green. Positive bis yellow, and negative b is blue. Colors can be described numericallyusing numerical values for L, a, and b. Differences between two colorscan be quantified for each of the individual L/a/b values (ΔL, Δa, Δb).Overall differences between two colors can be derived numerically basedon the three A values.

An alternative system, L*C*h color space, uses cylindrical instead ofrectangular coordinates. In this system, L indicates lightness, Crepresents chroma, and h is the hue angle. Chroma and hue are calculatedfrom the a and b coordinates of the L/a/b color space.

Patients with coronary artery blockages may have minimal symptoms and annormal electrocardiogram (ECG) while at rest. Cardiac stimulation may benecessary to identify irregularities. A cardiac “stress test” measuresthe body's ability to respond to external stress in a controlledclinical environment. The stress response is typically induced byexercise. The stress of exercise can also be approximated usingpharmaceutical stimulation (e.g. dobutamine or adenosine) for patientswho cannot easily perform physical exercises.

Cardiac stress tests compare the coronary circulation while the patientis at rest versus the same patient's circulation during maximum physicalexertion. The purpose is to identify any abnormal blood flow to themyocardium (heart muscle tissue). This can in turn be a reflection ofthe overall physical condition of the patient. Stress tests can be usedto diagnose coronary artery disease, and to assess patient prognosisafter a heart attack.

Cardiac stress tests involve heart stimulation, either by exercise on atreadmill, arm ergometer, exercise bicycle, or with pharmacologicalstimulation. The stress test is traditionally conducted with the patientconnected to an ECG, and in some cases also an imaging devise such as anechocardiograph. An ECG shows heartbeat speed and rhythm (steady orirregular). It also detects the strength and timing of electricalsignals as they pass through the heart. During a standard stress test,blood pressure is also checked. Patients may be asked to breathe into atube during the test to monitor breathing and gas exchange. A standardstress test shows changes in heart electrical activity, and whether theheart is getting enough blood during exercise.

In imaging stress tests, pictures are also taken of the heart duringexercise and recovery. Imaging stress tests can show how well blood isflowing in the heart, valve function, and how effectively the heartpumps blood when it beats. Imaging stress tests often useechocardiography (echo). Echocardiography uses sound waves to create amoving picture of the heart. A stress test echocardiogram can show areasof poor blood flow in the heart, dead heart muscle tissue, and areas ofthe heart muscle wall which are contracting poorly (e.g. due to heartattack damage or insufficient blood flow). Imaging stress tests usingradioactive dye are also available. Imaging stress tests are generallyconsidered better at identifying heart disease than non-imaging tests,but are more costly.

Over the course of a stress test the level of mechanical stress isprogressively increased, such as by increasing exercise resistanceand/or speed. The technician or attending physician monitors outwardsymptoms and blood pressure response. Exercise may continue until thepatient indicates that they wish to stop, or until a “peak exercise”threshold is attained. In the widely used Bruce Protocol (see below),peak exercise is defined by patient heart rate. Specifically, bysubtracting the patient's age from 220 and multiplying the result by85%. ([220−Age (years)]*0.85=Peak Heart Rate (in beats per minute)).Patients in poor cardiovascular health will typically reach their peakexercise heart rate relatively quickly during exercise. Fit patientsrequire more strenuous exercise to reach a given heart rate.

The Bruce protocol is a particular diagnostic stress test used in theevaluation of cardiac function, developed by Dr. Robert Bruce. A Bruceprotocol stress test involves walking on a treadmill while the heart ismonitored by an electrocardiograph with electrodes attached to the body.Ventilation volumes and respiratory gas exchanges are also monitoredbefore, during, and after exercise. Treadmill speed and inclination areincreased over the course of the test (e.g. every three minutes) untilthe patient signals that they need to stop. Typically during a BruceProtocol, heart rate and perceived exertion are taken every minute, andblood pressure is measured at the end of each stage (i.e. every threeminutes).

Doctors commonly classify patient heart failure according to theseverity of their symptoms. One common system is the New York HeartAssociation (NYHA) Functional Classification. It places patients in oneof four categories based on how much they are limited in their physicalactivity. Class I: No limitation of physical activity. Ordinary physicalactivity does not cause undue fatigue, palpitation, dyspnea (shortnessof breath). Class II: Slight limitation of physical activity.Comfortable at rest. Ordinary physical activity results in fatigue,palpitation, dyspnea (shortness of breath). Class III: Marked limitationof physical activity. Comfortable at rest. Less than ordinary activitycauses fatigue, palpitation, or dyspnea. Class IV: Unable to carry onany physical activity without discomfort. Symptoms of heart failure atrest. If any physical activity is undertaken, discomfort increases.

Acetylcholine is believed to dilate normal blood vessels by promotingthe release of a vasorelaxant substance from the endothelium(endothelium-derived relaxing factor). Paradoxical VasoconstrictionInduced by Acetylcholine in Atherosclerotic Coronary Arteries, P LLudmer et al., N Engl J Med. 1986 Oct. 23; 315(17):1046-51. This articlereports that in each of four normal coronary arteries, acetylcholinecaused a dose-dependent dilation from a control diameter of 1.94+/−0.16mm to 2.16+/−0.15 mm with the maximal acetylcholine dose (P less than0.01). In contrast, all eight of the arteries with advanced stenosisshowed dose-dependent constriction, from 1.05+/−0.05 to 0.32+/−0.16 mmat the highest concentration of acetylcholine (P less than 0.01), withtemporary occlusion in five. Five of six vessels with minimal diseasealso constricted in response to acetylcholine. All vessels dilated inresponse to nitroglycerin, however. The study concluded that paradoxicalvasoconstriction induced by acetylcholine occurs early as well as latein the course of coronary atherosclerosis. The findings suggested thatabnormal vascular response to acetylcholine is indicative of a defect inendothelial vasodilator function, and may be important in thepathogenesis of coronary vasospasm. Related principles are understood tounderlie the “wet run” protocol, described below.

Published Patent application US 2014/0378779 (Freeman et al.) disclosescomputer-based systems and techniques for analyzing skin colorationusing spectral imaging to determine a medical condition of anindividual. Freeman also teaches providing feedback to a rescuer orother medical professional based on the colorimetric properties of thepatient's skin. Freeman Abstract and paragraph [0002].

Freeman discloses measuring skin color as quantified using an L/a/bcolor scale. Freeman FIG. 6, paragraphs [0093]-[0097], etc. It alsoteaches that a spectrophotometer can be used to monitor the color ofpatient skin surfaces, among other possible devices. Freeman [0085],[0097]. Obtaining the color information can include obtaining baselinecolorimetric properties based on an intensity of light radiationreflected from the individual's skin, applying a stimulus configured toproduce a change in the colorimetric properties of the individual'sskin, and obtaining one or more additional measurements of thecolorimetric properties at times selected to capture changes in thecolorimetric properties of the individual's skin based on the appliedstimulus.

U.S. Pat. No. 7,620,212 (Allen et al.) relates to electro-opticalsensors for use in biometric analysis of optical spectra of tissue.Allen 1:52-1:56. Devices according to Allen can include a number offorms having a variety of functions. Allen largely focuses on usingbiometric methods to determine individual identities and/or demographicinformation such as age and sex. Allen also discloses using spectraldata to determine physiological states of human patients based onspectral variation. Allen 4:17-4:21. Spectrometers can be used to detectspectroscopic changes in skin color to determine physiological states inpatients. This functionality can be used as a stress detector or as alie detector. Allen discloses that stress in humans can cause changes inskin color, such as redenning, which can be detected spectroscopically.The changes in skin color are believed to result from changes in bloodflow in the tissue as a result of stress. Allen 18:14-18:40.

U.S. Pat. No. 5,671,735 (MacFarlane et al.) discloses a method andapparatus for determining the condition of a test subject using a colormeasuring instrument to detect changes in a color factor indicative of acondition such as a disease, ageing, etc. For example, a medicalcondition such as hyperbilirubinemia that affects skin color can bedetected. Color factors such as Hunter b and L can be measured for thesubject's skin. For predetermined ranges of one color factor, inparticular L, changes in the other color factor, e.g. Hunter b, abovepredetermined levels are indicative of the medical condition. Sequentialcolor readings can indicate the presence or absence of a condition basedupon changes in the measured color factor, or lack of changes, overtime.

When a medical condition affecting skin color is detected in a procedurelike that described for hyperbilirubinemia, the measuring of skin colorcharacteristics preferably continues at regular intervals until thesymptomatic color characteristic abates sufficiently to indicate theindividual's recovery from the medical condition. In the case ofhyperbilirubinemia, phototherapy is administered once a sufficientchange in Hunter b is observed to indicate the jaundice symptomatic ofhyperbilirubinemia. Throughout the course of phototherapy, the Hunter band L color characteristics are continually monitored until the jaundicehas been eliminated and treatment can be discontinued. MacFarlane2:66-3:9.

U.S. Pat. No. 7,483,733 (Shani et al.) discloses a non-invasive methodand apparatus to detect and monitor medical shock. A color sensor isused to detect skin color changes from pink to white (when the skin isdepressed to expel blood) and then back to pink (as blood returns tocapillaries when pressure is removed) in the relevant skin area. Thetime required for the skin to return to a pink color (i.e. CFT—capillaryfilling time) is determined. Slow recovery to an oxygenated pink coloris indicative of shock.

U.S. Patent Application Publication 2016/0073886 (Connor) discloseswearable spectroscopic sensors for measuring food consumption. ConnorFIG. 19 shows an example of a wearable device for the arm with aplurality of close-fitting biometric sensors.

U.S. Pat. No. 5,564,417 (Chance '417) teaches a wearable tissuespectrophotometer for in vivo examination of tissue of a specific targetregion. Chance '417 1:12-1:14. The spectrophotometer includes a phasedetector for measuring a phase shift between the introduced and detectedlight, a magnitude detector for determination of light attenuation inthe examined tissue, and a processor adapted to calculate the photonmigration pathlength and determine a physiological property of theexamined tissue based on the pathlength and on the attenuation data.

Chance '417 describes a path length corrected oximeter that utilizesprinciples of continuous wave spectroscopy and phase modulationspectroscopy. The oximeter is a compact unit constructed to be worn by asubject on the body over long periods of activity. The oximeter is alsosuitable for tissue monitoring in critical care facilities, in operatingrooms while undergoing surgery, or in trauma related situations. Theoximeter is mounted on a body-conformable support structure placed onthe skin. Chance 1:52-1:61.

U.S. Pat. No. 5,402,778 (Chance '778) discloses a system for examinationof a relatively small volume of biological tissue of interest usingvisible or infra-red radiation and a spectrophotometer. Thespectrophotometer is a continuous wave spectrophotometer, a phasemodulation spectrophotometer, or a time-resolved spectrophotometer.Chance '778 Abstract. In one example a human finger is inserted into ahollow cylinder, an the optical properties of the finger are measured bya spectrophotometer.

U.S. Pat. No. 8,082,015 (Yodh et al.) discloses a device, system, andmethod for determining the characteristics of deep tissue. Blood flowrate characteristics are measured as a function of light fluctuationscaused by the tissue, while the oxygenation characteristics are measuredas a function of transmission of light through the tissue with respectto the wavelength of light. The tissue characteristics may be measuredduring times of varying levels of exercise intensity. Yodh Abstract. Theinvention relates to methods and apparatus for measuring the flow ofblood and oxygenation characteristics using diffuse opticalspectroscopy. Yodh paragraph 1:18-1:21. Generally, the measurementtechniques derive tissue optical properties, for example, hemoglobinconcentration and blood oxygen saturation from diffuse reflectionspectroscopy (DRS) measurements, and blood flow from diffuse correlationspectroscopy (DCS) measurements. Yodh 5:20-5:24.

The above references are incorporated by reference, and should beconsidered as resources to support and assist implementation of theinvention except to the extent that any references may providedefinitions which directly conflict with definitions herein.

SUMMARY OF THE INVENTION

One aspect of the invention is a wearable color detector device formonitoring a patch of skin on a patient to detect and quantify colorchanges. “Color detector” refers to colorimeters, spectrophotometers,and equivalent devices capable of measuring at least red wavelengthlight. Color data may be saved on the device, or wirelessly transmittedto a remote storage module. The device includes a compact colormeasuring device (such as a spectrophotometric colorimeter) positionedon a patient for monitoring the skin surface. In one embodiment thedevice can be positioned on any area of a patient's skin, such as on arear shoulder blade or scapula, typically in a clinical setting. Inanother embodiment, the device is provided on a wrist band or in awatch-like form which the patient can wear for longer periods, with thecolor detector positioned against skin on the patient's wrist. The colordetector may communicate with a computing and/or storage device viaBluetooth, a USB cable connection, or other suitable means.

A light and color measuring device such as a spectrophotometercolorimeter apparatus is provided for tracking one or more physiologicalcondition of a subject based on skin color changes. The color detectordevice may include an input for receiving light from the subject's skin,the light having a characteristic color that varies with at least onephysiological condition of the subject, an output for outputting datacontaining information corresponding to the characteristic color of thelight received at the input at selected times, and data processing meansfor converting the light received into the data. A mounting means may beprovided for mounting the color detector to the subject at a locationand in a manner for placing the input adjacent a selected area of thesubject's skin. A data storage means is operatively connected to theoutput for storing the data for multiple selected times.

The color detector device can be used to monitor patient reactions tostimuli such as physical exercise or pharmaceuticals. Typically,quantitative L/a/b color scale measurements are taken over time on thesame skin surface before, during, and after a treatment. The inventionis not limited to a particular color quantification system. Skin colorchange and perfusion information is used to help tailor a treatmentregimen for the patient, such as prescribing medication and exercise.

In one aspect, a color detector is placed on a patient's scapula whilethey perform a treadmill “stress test” under medical supervision. Forexample, the “Bruce Protocol” inclined treadmill stress test where speedand incline are incrementally increased over time. Vital signs and colordetector measurements are taken every minute starting at time zero, inaddition to recording subjective descriptions of how the patient feels.When the patient terminates the stress test the treadmill is stopped andthe patient sits down, starting the recovery phase of the stress test.Vital signs and color detector measurements continue to be taken everyminute starting at recovery time zero, such as for the first ten minutesof recovery.

In another aspect, a color detector is used to monitor a patient duringa surgical or catheter procedure, or during a medical crisis such as inan ambulance or emergency room.

It has been determined that, broadly speaking, greater increases in skincolor (especially an increase in “redness”) and blood perfusion duringthe course of the stress test indicates better cardiovascular health.Less healthy individuals have relatively less color change for a givenstimulus, or even a reduction in redness reflecting inadequateoxygenation. Healthy patients are able to achieve greater metabolicoxygen consumption during the test, which is accompanied and facilitatedby widespread vascular dilation and increased redness in the skin (dueto capillary dilation and increased blood flow). This color change isoften too subtle to detect visually, and cannot be quantified visually.Therefore, methods using color detectors/light detectors such asspectrophotometric colorimeters to measure and quantify redness levelshave been devised.

The instant invention includes methods, computer programs, devices, andarrangements for performing patient diagnosis, treatment, and monitoringusing “dry runs” and/or “wet runs” as detailed herein. The inventionincludes methods and arrangements for detecting and quantifying skinperfusion and capillary dilation, changes in skin redness, and computerprograms and colorimeters for use therewith. The invention furtherincludes methods and arrangements for assessing the effects of exerciseand pharmaceuticals.

The invention includes methods and related devices for determining a redshift for a patient during a stress test. For example, methodscomprising:

(A) applying a wet run solution to a skin surface of the patient, saidskin surface receiving wet run solution comprising a testing area of theskin surface; wherein the wet run solution comprises, for example,acetylcholine;

(B) positioning a color detector on the patient after said applicationof wet run solution, wherein the color detector (e.g. colorimeter orspectrophotometer) comprises an input for receiving light, and whereinthe input is positioned to receive light from said test area;

(C) making and saving a baseline color measurement of the testing areausing the color detector, said baseline color measurement comprising abaseline skin redness level of the testing area;

(D) initiating an exercise protocol after the baseline colormeasurement, wherein the exercise protocol comprises the patientengaging in physical exercise;

(E) making and saving a plurality of exercise color measurements of thetesting area at different times during the exercise protocol, saidexercise color measurements each comprising skin redness levels;

(F) ending the exercise protocol by the patient ending the physicalexercise, such as because patient cannot continue or because a targetheart rate has been achieved;

(G) after the exercise protocol ends, beginning a recovery phase, withthe patient resting during the recovery phase such as by sitting orlaying down;

(H) making and saving a plurality of recovery color measurements of thetesting area at different times during the recovery phase, said recoverycolor measurements each comprising skin redness levels; and

(I) calculating the red shift for the patient, the red shift beingcalculated by comparing the baseline skin redness level and one of amaximum skin redness level and a minimum skin redness level saved duringsaid exercise protocol and recovery phase. For example, the maximum orminimum redness value from exercise color measurements and/or therecovery color measurements.

Preferred methods also include the exercise color measurements and therecovery color measurements being made at evenly spaced time intervals,the intervals being from 10 seconds and five minutes or from thirtyseconds to three minutes.

The methods can also include providing an EKG machine, and collectingEKG data for the patient during at least the recovery phase.

The wet run solution may comprise acetylcholine and at least one ofalcohol and water. The wet run solution may also or instead compriseacetylcholine and at least one of petroleum jelly and an oil.

The exercise protocol may include the patient using at least oneexercise machine selected from a treadmill, a stationary bicycle, anelliptical trainer, and an arm ergometer. The exercise protocol may bethe Bruce protocol.

The method may include performing the steps described above before, andthen again after, beginning a treatment comprising administration of apharmaceutical or biologic medicine to assess the efficacy of thetreatment. The second test may be at least one day, or a plurality ordays, after initiation of the treatment. The treatment preferablyincluded the patient receiving at least one dose of a pharmaceutical orbiologic each day.

The skin surface monitored for the above methods may be a back, arm,wrist, or chest of the patient.

Preferred exercise protocols comprise increasing at least one of a speedand a resistance of the physical exercise one or more times, orrepeatedly, at intervals, during the stress test.

The color detector may comprise an attachment element for reversiblyattaching the color detector to a patient. The color detector can bephysically attached to the patient with the attachment element such thatthe input for receiving light remains positioned at the testing areaduring the exercise protocol and/or the recovery phase.

The above methods may also include providing a second color detectorcomprising a respective second input for receiving light, andpositioning the second color detector such that the second input ispositioned to receive light from a different second test area, thesecond test area being a different part of the skin surface of thepatient, where wet run solution is not applied to the second testingarea. During performance of the steps (C)-(H), a plurality of dry runcolor measurements are made and saved using the second color detectorcomprising skin redness level at the dry second testing area. The dryrun measurement made during performance of said steps (C)-(H), using thesecond color detector may comprise: (i) a dry run baseline colormeasurement taken before initiating the exercise protocol; (ii) aplurality of dry run exercise color measurements taken at differenttimes during the exercise protocol; and (iii) a plurality of dry runrecovery color measurements taken at different times during the recoveryphase.

The invention also includes devices for determining a maximum red shiftfor a patient during a stress test according to any of the methodsdescribed herein. The device may comprise a processor and a memory, andmay be operatively linkable to receive color measurement data from atleast one color detector, the color measurement data comprising skinredness level data measured during a stress test with a patient. Thedevice may also be configured to calculate the maximum red shift, usingsaid color measurement data, by comparing the baseline skin rednesslevel and the maximum or minimum skin redness level saved during saidexercise protocol and recovery phase.

Additional arrangements of the invention include a color detector, and aconsole comprising a processor and a memory. Preferably the colordetector is operatively linkable to the console such that the consolecan receive color measurement data from the color detector, the colormeasurement data comprising skin redness level data measured during astress test with a patient. The same arrangements may be configured tocalculate maximum or minimum red shift, using said color measurementdata, by comparing the baseline skin redness level and the maximum orminimum skin redness level saved during an exercise protocol andrecovery phase.

The invention also includes wearable arrangements for determining a skinredness for a patient during a stress test, and methods using wearablearrangements. Such arrangements may include a color detector, a mountingelement, a processor, and a memory. Typically the color detector isoperatively linked to the processor and the memory for transmittingcolor measurement data comprising skin redness level data during thestress test. A mounting element for the color detector may be configuredfor reversibly attaching at least the color detector to a patient, andusing one or more of a belt, a wrist band, an adhesive, hook-and-loopfasteners, an elastic band, and a buckle. Color detectors may beincorporated into or attached inside of a shirt or other item ofclothing such that they can contact an appropriate skin area. Wet runsolutions and chemicals can also be incorporated into the garment itselfor a sorbent carrier positioned inside the garment in the vicinity of awet run color detector.

Arrangements may be embodied as a color detector module comprising thecolor detector and a transmitter worn by the patient during exercise.Color measurement data may be wirelessly transmitted from the colordetector module to a storage module comprising a memory during thestress test or exercise protocol where it is received and saved. Thestorage module may be a portable device such as a smart phone, or aremote system such a computer. Data may also be stored locally in otherembodiments, or transmitted to a smart phone.

In some methods according to the invention the redness of the testingarea of the skin surface declines during the exercise protocol. In suchcases calculating the red shift may comprise comparing the baseline skinredness level with a minimum skin redness level measured during exerciseor recovery, thereby determining a negative red shift value. The patientmay be diagnosed as having unsatisfactory cardiovascular health based onthe negative red shift value.

In other methods, the redness of the testing area of the skin surfaceincreases by at least 20%, 30%, or 50% during the exercise protocol.Calculating the red shift then comprises comparing the baseline skinredness level with the maximum redness level during exercise orrecovery, thereby determining a positive red shift value of at least+10%, +30%, or +50% as applicable. The patient may be diagnosed ashaving satisfactory cardiovascular health in response to the positivered shift value of at least +10%, +30%, or +50%. Devices configured forstoring data and making such calculations and determinations are alsocontemplated.

The invention includes displaying on a display a graph plotting skinredness levels over a period of time. For example, a graph comprising abaseline color measurement, a plurality of exercise color measurements,and one or more recovery color measurements. Graphical displays may alsocompare wet run vs. dry run measurement for a patient over the course ofa stress test.

The various features of novelty which characterize the invention arepointed out with particularity in the claims annexed to and forming apart of this disclosure. For a better understanding of the invention,its operating advantages and specific objects attained by its uses,reference is made to the accompanying drawings and descriptive matter inwhich a preferred embodiment of the invention is illustrated.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings:

FIG. 1 is a spectrophotometer;

FIG. 2 is an illustrative graph of red shift over the course of a stresstest for three different normal patients;

FIG. 3 is an illustrative graph of red shift over the course of a stresstest comparing healthy and unhealthy patients;

FIG. 4 is a second illustrative graph of red shift over the course of astress test comparing healthy and unhealthy patients;

FIG. 5 is an illustrative graph comparing normal and sawtooth red shiftcurves;

FIG. 6 is a graph of red shift data for a very healthy patient during astress test;

FIG. 7 is a graph and table of red shift data for a moderately healthypatient during a stress test;

FIG. 8 is a graph and table of red shift data for a second moderatelyhealthy patient during a stress test;

FIG. 9 is a graph and table of red shift data for an unhealthy patientduring a stress test;

FIG. 10 is a graph and table of red shift data for a second unhealthypatient during a stress test;

FIG. 11 is an illustrative graph of red shift data measured by wet anddry run methods during a stress test;

FIG. 12 is a second illustrative graph of red shift data measured by wetand dry run methods during a stress test;

FIG. 13 is a graph and table comparing wet and dry run measurements fora normal patient during a stress test;

FIG. 14 is a graph and table comparing wet and dry run measurements fora second normal patient during a stress test;

FIG. 15 is a graph and table comparing wet and dry run measurements foran unhealthy patient during a stress test;

FIG. 16 is a graph and table comparing wet and dry run measurements fora second unhealthy patient during a stress test.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Methods and devices according to this invention use one or morespectrophotometers, colorimeters, and/or other devices for detecting,measuring and quantifying color. Other devices which similarly measurecolor changes, especially changes in “redness” or a red/green colorcoordinate, are within the scope of the invention. Spectrophotometriccolorimeters are a preferred device. Where the term “color detector” isused in this disclosure, it should be understood to also include aspectrophotometric colorimeter, colorimeter, spectrophotometer, as wellas other equivalent devices, which will not be recited in each instancein the interests of brevity. Color measurements may be L/a/b values, thea value (red/green) only, R/G/B, or other known methods of colorquantification. While many color monitoring devices detect and record anumber of color parameters (e.g. L/a/b), preferred embodiments of thisinvention are primarily concerned with changes in the amount of redlight reflected. Thus, devices and methods which only measure red orred/green spectrum light are also contemplated. One or more lights maybe paired with a color measuring device.

FIG. 1 is an example of a spectrophotometer, a type of color detector.L, a, and b color readings for the hand of an individual holding thecolorimeter are visible on the display. Devices providing other outputssuch as RGB (red/green/blue) can also be used.

Color detector measurements are preferably taken at the same location onthe patient throughout the protocol. Less hairy and more easilyaccessible skin locations, such as the scapula, are preferred. The colordetector device may be fixed on the patient for the duration of theprocedure, or a color detector may be positioned at the measurement sitefor each reading and then removed. Color detector measurements aretypically recorded and saved in a readable medium.

Preferred methods include “wet runs” where skin surface being monitoredwith a color detector is first treated with a wet run solution, asexplained below. A preferred wet run solution includes acetylcholine asan active ingredient, in addition to water or other carriers.

“Dry runs” refer to protocols where the skin being monitored is nottreated with a wet run solution, as detailed below, and also haveapplications.

Skin Color Change as Vascular Diagnostic Indicator

Work underlying this invention has found that change (or lack of change)in skin color in response to certain stimuli can be used to gagevascular health. This is at least partially due to the fact that thesame type of cells—endothelial cells—line substantially the entirevascular system, from the largest arteries down to the capillaries. Theendothelium is a specific type of epithelium which lines the interiorsurface of blood vessels and lymphatic vessels, forming an interfacebetween circulating blood (or lymph) and the rest of the circulatoryvessel and body. The endothelium is a thin layer of simple squamouscells called endothelial cells. Endothelial cells in direct contact withthe blood are called vascular endothelial cells. Endothelium making upthe interior surfaces of the heart chambers is also known asendocardium. Identification of reduced functionality in capillaryendothelium, as disclosed herein, can be used to identify vasculardisease less invasively, and earlier in time, than known alternativemethods.

In healthy individuals, physical exertion quickly leads to increasedheart rate, blood flow, and blood vessel dilation. This facilitatesincreased oxygen delivery during exercise. Blood vessel dilation in thiscase is systemic, including both larger arteries and small capillariessuch as those supplying blood and oxygen to the skin. Skin capillarydilation brings greater amounts of red oxygenated blood near the skin,which in turn increases the red color of the skin (aka “red shift”,“alpha shift”, or Δa) as compared to the resting state. This phenomenonhas been observed across patients having various different skin tones.This color change is generally too subtle to detect visually, and cannotbe quantified visually. Therefore, methods using light detectors such asspectrophotometric colorimeters to measure and quantify redness levelshave been devised.

In healthy individuals, when exercise ends, heart rate, blood flow, andblood vessel dilation also return to resting levels relatively quickly.This, in turn, causes skin red color levels to return to resting colorrelatively quickly.

In patients with unhealthy circulatory systems, the dilation reactionfrom exercise is both reduced and delayed, reflecting a generally poorand slow physiological response to support physical exertion. Thevascular dilation response (to help increase blood delivery) occurs moreslowly, and to a lesser extent, than in healthy individuals. Thus theincrease in blood flow to skin capillaries, and corresponding increasein red color, is reduced and delayed in unhealthy individuals (i.e. thepeak Δa is low). In more severe cases, there may be little or nodetectable increase in skin perfusion and redness. Patients havingsevere vascular disease (e.g. stenosis greater than 75%) may actuallyexhibit a negative red shift in response to exercise. The ability of theheart to pump sufficient blood to adequately perfuse the body forexercise is lower in significant part because of poor dilation inresponse to exercise throughout the vasculature, including in thecapillaries. When exercise ends, unhealthy patients also take longer toreturn to resting vessel dilation state and red levels. This reflects agreater need to compensate for oxygen deficits created during exercise,reduced ability to compensate for those oxygen deficits, and generallyslower reactions rates.

In a healthy individual, exercise triggers a significant positive redshift (i.e. increase in skin redness) from the resting baseline whichcan be represented as a curve on a graph. See FIG. 1. The slope orsteepness of this increase and decrease will vary, but the general upand down curve is typical among healthy individuals. This holds trueusing both wet and dry run methods, though the degree or red shift isusually greater with wet run methods in healthy individuals. Steeperinclines and a shorter time to peak positive red shift are correlatedwith better cardiovascular health. This is because steep inclinesindicate a rapid body response to exercise to increase blood perfusion,and distribute more blood and oxygen when it is needed.

FIGS. 2-5 represent typical and idealized graphs of red shift over timeduring stress tests to illustrate principles identified over the courseof numerous procedures with individual patients. Graphs of individualpatent red levels, recorded periodically (e.g. every minute) may be lesssmooth and, in some cases, may deviate from the idealized-but-typicalexamples which are provided for illustrative simplicity.

FIG. 2 shows illustrative graphs of red shift over time for threetypical idealized “normal” patients undergoing colorimetric monitoringduring exercise. Units are not specified in these illustrative graphs.The start of exercising is indicated by the left origin of each curve.Exercise continues until peak exercise, indicated by the respectivepoints at the top of each curve. Peak exercise may be determined basedon reaching a predicted maximum heart rate and is frequently (but notalways) maximum positive red shift. After this point recovery beginsand, typically, skin color begins to return to baseline at the right endof each curve. All three patients in FIG. 1 are considered normal andvery healthy to reasonably healthy because they have a substantialpositive red shift (indicating increased perfusion) during the course ofthe activity. Patient A is in the best condition of the three becausethey reach peak red shift (indicating elevated perfusion) the mostquickly. Patients B and C are the second and third best cardiovascularhealth, in that order, based on the time required to reach peak redshift.

FIG. 3 shows illustrative graphs of red shift over time as four patientsin varying states of vascular health perform an exercise routine. Timeand red shift units are arbitrary, but all curves are on the same scalefor comparison purposes. The patient represented by the tallest curve 10is in the best cardiovascular health, exhibiting fast and substantialred shift during exercise. At the other extreme, the patient representedby curve 16 has the poorest vascular health, managing only a small andslow positive red shift during exercise. This indicates that they haveonly weak ability to increase blood and oxygen flow during exercise, andthat what response they are able to achieve is slow. The patientsrepresented by curves 12 and 14 are the second and third healthiest,respectively, based on the size of their red shift peaks and timesrequired to achieve peak perfusion. Healthier patients also usuallyrecover (i.e. return to baseline redness and perfusion) more quickly.

FIG. 4 illustrates similar principles as FIG. 3, comparing stress tests(e.g. wet run) by four patients in varying states of cardiovascularhealth. Patient A is healthiest, having the greatest red shift which isalso achieved quickly, followed by rapid recovery and return tobaseline. Patient D is in very poor cardiovascular health, and actuallyhas a negative red shift during stress test, indicating a pallid colorand inadequate perfusion.

“Red shift” refers to change in skin redness. Different individuals havedifferent complexions and different baseline/resting red levels in theirskin, but red shift can be quantified in relative terms. For example, interms of a % change in the red (A) value the L*a*b* color space orHunter L/a/b color space, although other red quantification systems maybe applied similarly. Typical stress test peak red shift valuesindicative of good cardiovascular health would be +10%-+100%, +30%-+70%,+10% or more, or +30% or more compared to resting. Stress test peak redshift (or in the case of negative red shift, minimum) values indicativeof poor cardiovascular health include +10% or less (including negativeshifts), 0% or less (i.e. no change or negative red shift), +10% to−100%, or 0% to −100%. Negative red shift values may be descriptive of apatient who exhibits a “pallid” or “white” appearance in response toexercise, depending on normal complexion.

A “sawtooth” red shift curve also indicates cardiovascular illness. SeeFIG. 5. A sawtooth curve is characterized by having multiple pronouncedpeaks over the course of a single exercise session/single stress test.For example, a stress test where red levels go up, down again by atleast 25% or at least 33%, and back up again one or more times duringthe course of a continuous exercise session. This is evidence of anunsteady, vacillating vascular response to stress. Healthy patients mayshow slight up-down-up activity as a result of normal variation orreaction lag, reading margin of error, etc. and still be considerednormal. “Sawtooth” patterns refer to curves with highly pronouncedup-down-up vacillation, e.g. including redness increases, then declinesof at least 25% or at least 33%, followed by further increases of atleast 25% or at least 33%.

In particular, sawtooth red shift patters have been associated withobstructive artery disease during the work supporting this invention.Sawtooth red shift patterns during a stress test are indicative thatfurther diagnostic steps for obstructive coronary artery disease, andpotentially recommend treatments such as aspirin, other medication,balloon angioplaty, stent placement, or coronary bypass surgery asneeded. In contrast, “smooth” curves having low or negative red shiftsbut only a single peak are associated with non-obstructive coronaryartery disease, such as tachycardia or malignant ventriculararrhythmias.

This invention includes methods of diagnosing cardiovascular health bymeasuring skin red shift during exercise, most preferably using wet runmethods during a stress test, and comparing results with these typicalvalues. The invention also includes arrangements including colordetectors, computer programs, and processors configured for use withsuch methods. The invention also includes kits which include colordetectors and skin applications for performing wet run methods.

Red shift based methods according to this invention can be used toidentify cardiovascular improvement (when present) due to medication,exercise regimens, open heart surgery, catheter surgery, stenting, newdiets, or other procedures intended to improve vascular health. Thegoal, broadly, is that the patient has a response (e.g. a red shiftcurve per above) corresponding to a “healthier” person after thetreatment.

Our work has identified previously unknown differences in the reactionsof healthy and unhealthy individuals to acetylcholine and othervasodilative substances when applied to the skin. Acetylcholine createsa significant and detectable capillary dilation and positive red shift(due to increased blood flow) when applied to the skin of healthyindividuals. Individuals with weaker circulatory systems, in contrast,have weaker or no dilation and red shift response to topicalacetylcholine.

As stated above, and without being bound by theory, acetylcholine isbelieved to dilate normal blood vessels by promoting the release of avasorelaxant substance from the endothelium (endothelium-derivedrelaxing factor). Paradoxical Vasoconstriction Induced by Acetylcholinein Atherosclerotic Coronary Arteries, P L Ludmer et al., N Engl J Med.1986 Oct. 23; 315(17):1046-51. This study reported that acetylcholinecaused a dose-dependent dilation in coronary arteries. It also reporteddose-dependant constriction in coronary arteries with advanced stenosis.Five of six vessels with minimal disease also constricted in response toacetylcholine.

Work leading to the instant invention identified previously unknownparallel responses to acetylcholine in healthy and unhealthy vasculaturebeyond the coronary artery, most notably in skin capillaries. Further,and importantly for the instant invention, correlation has beenidentified between the dilation reactions (or lack thereof) of largearteries and of capillaries within individual patients. This isunderstood to be at least partly due to the fact that large arteries andnarrow capillaries are all lined by endothelial cells which (1) havesimilar reactions to many stimuli, and which (2) are similarly limitedthroughout the circulatory systems in individuals with vascular disease.Healthier endothelium is believed to be more reactive to exercise andacetylcholine (for example) than unhealthy endothelium regardless ofwhere in the body it is located. In essence what occurs in capillariesnear the skin (or mucous membrane) is also occurring in the endotheliumin the heart.

Thus, it has been determined that vascular and endothelial health for apatient as a whole can be gauged by measuring capillary dilation in theskin based on subtle color changes. Novel methods and apparatus formeasuring capillary dilation in the skin, and for related diagnoses andtreatments, are discussed elsewhere in this disclosure.

The same principal applies to mucous membranes as to skin, with theadded advantage that the underlying vasculature (e.g. capillaries) aremore exposed to the surface than in typical skin (e.g. on the upperback). This provides more pronounced color changes and differentiationthan is obtained from regular skin. Further, for wet runs, mucousmembranes can have greater drug permeability. The disadvantage of mucousmembranes is that their locations often makes color detector positioningand monitoring more difficult and less practical. Nevertheless, thesubstitution of mucous membranes in place of patient skin is within thescope of the invention, and should be considered disclosed for allembodiments where practicable.

Typically and preferably, when a series of skin redness measurements arebeing made and compared, the same area of skin should be observed eachtime. Different areas of skin on a given individual can have differentshades and other variables (hair, texture etc.). Observing the samelocation minimizes the chance that factors other than perfusion,dilation, blood oxygenation etc. will result in different color readingsbetween measurements. For example, if a patient is undergoing stresstests before and after being administered a pharmaceutical, the colordetector(s) should be in the same location for each test. This ensuresan “apples to apples” comparison.

FIG. 6 is a wet run stress test curve showing red shift for a 40 yearold Marine who is in excellent cardiovascular health. The curve shows asubstantial and rapid increase in redness (redness A roughly doubling),followed by a rapid return to pre-exercise skin color and perfusion whenexercise ends.

FIG. 7 is a wet run stress test curve for a patient L.V. who is inreasonably good cardiovascular health, though to a lesser extent thanthe Marine in FIG. 6. Skin redness increases by approximately 39% fromexercise start to peak.

Note: The first portions of the graphs in FIGS. 7-10 showing increasesstarting from zero redness are artifacts and do not reflect patient data(skin redness will rarely, if ever, be zero).

FIG. 8 is a wet run stress test for a 50 year old female also in areasonable state of health. Skin redness increases approximately 66%from baseline to maximum.

FIG. 9 is a stress test for unhealthy patient P.E. Skin redness actuallydeclines by approximately 24% over the course of the stress test.

FIG. 10 is a second unhealthy patient J.F. Skin redness declines byapproximately 57%.

The principles and methods of this invention have been developed workingwith a large number of patients, and the specific patients and datashown FIGS. 6-10 are selected as illustrative examples.

Cardiovascular health as estimated by stress test red shift has beenfound to correlate well with cardiovascular health as determined withother more traditional methods, and has good predictive value whenfollow-up diagnostics are performed.

Dry Run Method

A “dry run” procedure refers to monitoring and diagnosis steps accordingto the invention which are performed without applying a chemicalsolution to the area of skin being observed by the color detector. Dryruns are sometimes used (as opposed to wet runs) for simplicity, such aswhen applying a chemical solution would be inconvenient or impractical.For example, it may be more practical to use dry run conditions whenperforming long term monitoring outside of a medical environment using aportable color detector.

An exemplary dry run is performed in a stress test lab in a medicalfacility. Before the procedure vital signs may be checked: e.g. heartrate, oxygennation, and EKG (baseline). Next, a baseline resting colordetector reading is taken. For example, L/a/b values can be recorded atbaseline at the patient's upper scapula, preferably while they aresitting or standing still and their heart exertion is at resting levels.

The patient then begins a stress test exercise regimen, such as the“Bruce protocol” which uses a treadmill. The Bruce Protocol is a threeminute interval stress test, starting at 10% incline at 1.7 miles perhour, changing to 12% incline after three minutes, increasing to 2.5miles per hour changing to stage three, then 14% incline at 3.4 milesper hour, then 16% incline at 4.2 miles per hour, and then 18% inclineat 5.1 miles per hour. Speed and incline can increase indefinitely intheory, though in practice patients actually needing stress testsgenerally cannot go beyond 18% incline and 5.1 miles per hour. The BruceProtocol is only a preferred example, and other stress test protocolscan be used with the invention. For example, exercise time intervals inthe ranges of 10 seconds-10 minutes, 30 seconds-5 minutes, 1 minute-4minutes, or 2 minutes-4 minutes, raising exercise resistance and/orspeed at each interval. The exercise protocol can include the patientusing, for example, a treadmill, a stationary bicycle, an ellipticaltrainer, an arm ergometer, or other known exercise devices.

Color detector readings are made at regular intervals during the stresstest. For example, L/a/b readings (or just a readings or red lightreadings) may be taken every minute of the Bruce protocol starting attime 0. Other vitals (blood pressure, heart rate, EKG, etc) can also bemeasured throughout the procedure at the same or different intervals,along with subjective statements regarding how the patient feels such aschest discomfort or shortness of breath. Reading interval ranges ofevery 30 seconds to every 2 minutes, every 30 seconds to every 4minutes, and every 10 seconds to every 5 minutes are examples within thescope of the invention.

The exercise portion of the test typically ends when the patientindicates they want or need to stop, but can also be ended at “peakexertion”. The patient immediately sits down, which begins the recoveryportion of the procedure—i.e. recovery time 0. A color detector readingis made, as well as any vitals as described above and a subjectiveevaluation of how the patient feels. Periodic readings continue duringthe recovery period. For example, every minute up to 10 minutes inrecovery.

Color detector readings are preferably taken at the identical site onthe patient throughout the exercise and recovery portions of theprocedure. For example, on the right superior portion of the scapula, oron the arm or wrist using a worn color detector.

In some embodiments, myocardial performance index (LV) (Tei Index) isevaluated before and after each run. Tei Index is an index thatincorporates both systolic and diastolic time intervals in expressingglobal systolic and diastolic ventricular function. Determining TeiIndex describes the systolic (squeezing) and diastolic (relaxation)function of the heart and is correlated with the values of the colordetector.

Wet Run Method

“Wet runs” can be performed according to the same general protocoldescribed above for dry runs, which are incorporated herein but will notbe fully repeated for brevity. The difference is that for wet runs theskin area being measured with the color detector is wetted with achemical solution (a.k.a. “Wet run solution”). For example, a solutionof one or more chemicals (e.g. acetylcholine and/or thrombin) in water,alcohol, petroleum jelly, or saline. The solution can be applied bywiping or covering the area with a wet gauze pad. The solution may beapplied once at the beginning of the procedure before the color detectoris positioned on the skin, or applied more than once throughout theprocedure. Suspensions of effective chemicals (as opposed to solutions),viscous spreadable chemical applications, lipid-carrier compounds, andpotentially non-wet applications of effective chemicals are alsocontemplated.

As mentioned, skin redness increases both more, and more quickly, inhealthy patients than in patients with vascular disease. Acetylcholine(and other applicable chemicals) increase the color contrast betweenhealthy and unhealthy individuals, which has been found to facilitatebetter colorimetric diagnoses. For example, in a healthy individual, thepositive red shift (a.k.a. “alpha shift”, a.k.a. Δa) is greater at agiven exertion level in a wet run than in a dry run. An unhealthyindividual, in contrast, will still have low, negligible, or evennegative red shift during exercise in a wet run. Wet run methods, whenavailable, are generally preferred to dry runs because they increase thecolor difference between healthy and unhealthy individuals.

Wet runs can also be used as a partial substitute for exercise in aclinical setting, such as for patients who are not physically able toperform stress test exercises. The chemical alone provokes the samegeneral types of differential responses as stress test exercise. Forexample, in a healthy at-rest individual, acetylcholine alone causesskin capillary dilation, which increases blood perfusion and (becauseblood is red) causes the skin to become more red. In an unhealthyindividual, the acetylcholine alone will cause only low, negligible, oreven negative red shift. Thus the differential reactions to applicationof acetylcholine (for example) can be used to assess vascular health orthe effectiveness of medication even without a stress test.

Acetylcholine is understood to dilate normal blood vessels, but to notdilate or to constrict vessels subject to various deleterious conditionssuch as stenosis. See discussion of Paradoxical Vasoconstriction Inducedby Acetylcholine in Atherosclerotic Coronary Arteries above. Withoutintending to be bound by theory or to limit the scope of the invention,the instant methods and solutions take advantage of related propertiesunderstood to exist in skin capillary vasculature.

In both wet and dry runs, each procedure can be repeated more than oncein order to confirm results, reduce testing error, and identify lessreliable outlier data.

Wet run solution is typically applied to a relatively small area of thepatient comparable to or somewhat larger in size than the input windowof the color detector to be used for the wet run. For example, wet runsolution may be applied to a body area of 1-10, 1-100, 0.1-100, or1-250, or 5-400 square centimeters.

Wet run solution is preferably applied to the skin shortly before wetrun monitoring begins. For example, the same day as the wet run, lessthan an hour, less than twenty minutes, less than five minutes, or lessthan one minute before the color detector is positioned over the areaand/or the wet run color detector monitoring begins. Additionalpreferred time ranges for applying wet run solution are 1-60 seconds, 1second-five minutes, 1 second-20 minutes, 10 seconds-10 minutes, 30seconds-20 minutes, 1-10 minutes, and 1-60 minutes before monitoring.

Chemical Stress Testing

Pharmaceutical stimulation can be used instead of exercise for patientswho would have difficulty using a treadmill or other exercise methods.Chemical stress tests typically use intravenous medication (e.g.dobutamine, dipyridamole, or adenosine) with an imaging technique(isotope imaging or echocardiography). The medication increases theheart load, as opposed to physical exercise. The chemical stress causesnormal coronary arteries to dilate, while the blood flow in a blockedcoronary artery is generally reduced. This reduced blood flow in theblocked artery reduces movement of the affected wall (as seen byechocardiogram), or reduces isotope uptake (in a nuclear scan).

Dry and (preferably) wet run color detector observation can both be usedto measure red shift before, during, and after chemical stimulation inchemical stress tests, applying the same principles and general methods.Patients in better cardiovascular health are expected to have greaterpositive red shift in response to chemical stimulation than patients inpoor health. Color detector measurements can be made before chemicalstimulation (baseline), at intervals during chemical stimulation, andafter chemical stimulation is ended. Color detector monitoring can beapplied in addition to traditional EKG and/or imaging monitoring, or onits own.

The invention includes use of chemical stress testing together with wetrun methods, and with simultaneous wet run/dry run comparison methodsdiscussed in greater detail below. Stress testing with red levelmonitoring can be used before and after administering a pharmaceuticalto determine efficacy.

Wet Run Solutions

As mentioned above, acetylcholine solutions can be applied to the skinto increase the color contrast between healthy and unhealthyindividuals, which has been found to facilitate better colorimetricdiagnoses. Colorimetric monitoring procedures which include the use ofsuch chemical solutions are described generally as “wet runs”. Chemicalsolutions for use in wet runs may also be termed “wet run solutions”.

Wet run solutions can be applied to the area of skin being monitored ina variety of forms and regimens. Typically the wet run solution will beapplied to the skin, and then the color detector is positioned on theskin either immediately or after a short waiting period for the solutionto soak in and take effect. In longer procedures the solution may beapplied repeatedly as needed.

Wet run solution may be applied by various known methods. A gauze pad orother absorbent material is wetted with the wet run solution, and thenwiped over or held against the skin. For example, an item soaked in wetrun solution may be held against the skin for at least 5, 10, 30, or 60seconds. The solution may also be brushed or sprayed on.

In one illustrative example, a half cup of 70% isopropyl alcohol ismixed with a half teaspoon of acetylcholine to make a wet run solution.Wet run solution may be prepared daily or even for each patientdepending on circumstances. Wet run solutions with the followingchemical amounts (by weight compared to total carrier/solvent) arecontemplated as non-limiting examples: 3-5%, 1-5%, 1-10%, 0.1-10%,0.1-25%, 0.01-5%, 0.01-25%, 5-50%, at least 0.1%, at least 1%, at least5%, at least 10%, and at least 20%.

While acetylcholine is a preferred wet run chemical, other drugs whichaffect endothelium constriction (“endothelial stimulatory compounds”)can also be used. The important factor is that the chemical(s) causeendothelium in both the arteries and capillaries to dilate in healthyindividuals, but not (or to a lesser degree) in individuals havingvascular disease. Endothelium-dependent vasodilators are generallyunderstood to be useful wet run chemicals. Endothelium-derived relaxingfactors (EDRF) are produced and released by the endothelium to promotesmooth muscle relaxation. The best-characterized EDRF is nitric oxide(NO). Without limitation, the following are also believed to be usefulas wet run chemicals individually or in combinations: adenosine,persantine, acetylcholine, serotonin, bradykinin, nitric oxidederivatives (e.g. Viagra® (sildenafil), Cialis® (tadalafil), Levitra®,(vardenafil)), phosphodiesterase type 5 (PDE5) inhibitors, mergonavine,ergometrine (a.k.a. ergonovine), arginine derivatives, citrulinederivatives, thrombin, thromboplastin, L arginine and argininederivatives, thiols, cysteine, glutathione, peroxynitrite, cysteine,glutathione, peroxynitrite, nitrosates, nitrosites, nitrosates glucose,nitrosates glucose, nitrosyl glucose, and/or transnitrosates. Wet runsolutions including these chemicals, and wet run procedures using suchwet run solutions, are contemplated for implementing the invention.

We recommend that when there is doubt, candidate chemicals can beevaluated as wet run chemicals by testing them on the skin ofindividuals known to have and not have vascular disease, and to confirmthe presence of differential dilation (as measured by red shift) betweenthose individuals as disclosed herein. Further, candidate chemicals canbe evaluated by testing differential dilation effects when the chemicalsare injected into coronary arterial circulation. See ParadoxicalVasoconstriction Induced by Acetylcholine in Atherosclerotic CoronaryArteries cited above. Candidate chemicals may be confirmed as havingdifferential dilation in healthy vs. vascular disease patients in boththe capillaries and the coronary arteries. This has the added advantageof confirming parallel reactions in the coronary arteries and the skincapillaries.

Various solvents or carriers can also be used. For example, water,alcohol (e.g. isopropyl, ethyl, methyl) alone or mixed with water,saline, phenols or phenol-derived solvents, petroleum jelly, lipids, andoils. Suspensions and dry and wet mixtures are also contemplated asalternatives to “wet run solutions”, so long as safe and effectivedelivery of one or more wet run chemicals to the skin is accomplished.

The wet run solution may advantageously be viscous, as opposed to fullyliquid, for some applications. Viscous solutions can be prepared using aviscous solvent or carrier (e.g. petroleum jelly, oils, or otherlipids), and/or high concentrations of chemical and relatively loweramounts of solvent. Viscous wet run solutions can stay on the skin forlonger periods without running off or evaporating. Viscous wet runsolutions may be used to provide a supply of chemical to the skin overlonger periods than conventional liquid solutions, providing some“extended release” function. For example, a viscous wet run solution(e.g. acetylcholine in petroleum jelly) may be applied as a thin layeron the skin and a color detector then placed over the same area toperform an extended wet run. For example, wet run solutions having totalviscosities of at least 0.1, 0.5, 1.0, or 2.0 Pa·s at room temperatureare contemplated.

Wet run solutions (or mixtures, emulsions, etc) using hydrophilliccarriers or solvents are also contemplated. Hydrophillic carriers areuseful to increase the skin and cell permeability of the wet runsolutions for improved transdermal drug delivery. For example, oils,fats, petroleum jelly, or paraffin. Some hydrophobic carriers/solventswill provide similar staying power/extended release advantages asviscous carriers/solvents discussed above.

In clinical trials wet run solutions have been prepared daily and/or foreach new patient, although such is not a requirement.

Wet run solution may be provided via a disposable transdermal patch,which may be positioned on the skin using adhesive.

Wet run solutions and chemicals can also applied to a garment, arm band,sorbent patch or other carrier which can be worn against the skin. Thewearable item may be combined with a wearable color monitoring device sothat wet run chemicals are provided to the skin in the immediatevicinity of the monitoring device, or could be worn and then removedbefore wet run color readings are taken. Wet run chemicals may beprovided to the wearable carrier as a solution, slurry, or other wetpreparation. Alternatively, undissolved or dry “wet run” chemical can beprovided in the carrier or patch to be dissolved as the patient sweatsduring exercise, facilitating skin absorption.

Aspects of this invention thus include wearable items which incorporateboth wet run chemicals and one or more color detectors positionedadjacent the same area(s) of the wearer's skin (e.g. adjacent, or within1 or 0.5 inches), and methods using such wearable items. One embodimentis a garment including a wet run color detector adjacent a wet runcarrier holding wet run chemical, and a dry run color detector at adifferent location. In a preferred embodiment the color detectors arepositioned in the garment (e.g. a shirt) near a user's back, upper back,or shoulder blades in mirror-image locations. The garment can be shapedand sized to hold the color detectors and carrier against the skin,and/or adhesives could be used to maintain the items against the skin.

Example 1—Stress Test Protocol

A 30 year old patient is administered exercise stress test and EKG. Thepatient exercises for a total of 15 minutes pursuant to the BruceProtocol. Color detector readings are taken on hairless area of rearshoulder or other accessible and hairless area. Baseline color detectorL/a/b reading of skin color is acquired before Bruce Protocol stresstest is initiated. The patient is started on treadmill at 1.7 mph, whichis increased over time per the protocol. L/a/b color detector readingsare taken at one to three minute intervals during the duration of theprotocol, and when patient ends the exercise. When exercise ends,patient sits down to begin the recovery phase. Color detector readingscontinue every one to three minutes for a five to twenty minute recoveryphase.

EKG is also monitored during exercise and recovery phase, and ST-T waveirregularities, if any, are identified. Doppler ultrasound imaging isalso used during recovery and correlated with EKG to identifyabnormalities. Specifically, tissue Doppler indices are evaluated on theseptal and lateral wall of the left ventricle underneath the mitralvalve. This allows the replication of objective evidence of ischemicthresholds seen on standard cardiovascular testing to be compared to thecolor detector data.

A dry run can be employed in the exercise and recovery phases, where thecolor detector is placed directly on patient skin during stress test andrecovers.

A wet run is employed instead of or in addition to the dry run. In wetrun a gauze pad soaked with chemical solution (e.g. acetylcholine inalcohol) is placed on the area of skin to be monitored. For example,application may be for 30 seconds, for 10 seconds to three minutes, forat least 5 seconds, for at least 15 seconds, or for another period oftime. Once the pad is removed the color detector is applied and colorreadings are made as described above.

Both wet and dry runs may be simultaneously used during the stress testand recovery. For example, using two color detectors, one on eachshoulder blade, during exercise and recovery.

Example 2—Color Detector Stress Test Identifies Coronary Artery Disease

A patient underwent a treadmill stress test with both wet runcolorimetric and (standard) EKG and image (echocardiograph) monitoring.Standard EKG and image results indicated normalcy. However, colorimetricspectrophotometer showed a negative red shift in the skin during astress test, which (correctly) indicated severe deficits in perfusion ofthe coronary circulation and arterial circulation of the heart.Follow-on examination determined that the patient had balanced ischemicheart disease (i.e. disease causing decreased blood flow to all threecoronary arterial areas of the heart). Thus in this case thecolorimetric stress test correctly identified severe coronary arterydisease which was missed by standard stress test methods.

Administering and Testing Medication

The effects, effectiveness, and correct dosing of medication can varysubstantially between individuals, and colorimetric analysis accordingto this invention is useful to measure and quantify individual reactionsbased on endothelial response and skin capillary dilation. Positiveeffects can be identified and confirmed, e.g. by increased red shiftduring exercise. Colorimetric methods can be used to identify a minimumdose needed to achieve a peak or satisfactory improvement, as determinedby improved red shift. This allows the physician to maximize positiveresults, while avoiding side effects and/or toxicity from unnecessarilyhigh drug doses.

Color detector methods according to this invention are particularlyrelevant to medications which treat vascular conditions such asAtorvastatin (Lipitor®), Rosuvastatin (Crestor®), and the like.

For example, a wet run may be performed on a patient before taking agiven medication, and one or more times after medication has beenstarted, to determine the vascular improvement (if any) provided by theregimen. The color detector(s) should be in the same position on thepatient for all of the tests for a consistent comparison. A greater redshift in an exercising wet run after medication has been started isindicative that the medication is having a beneficial effect on thecirculatory system as a whole. When wet run results are disappointing,dose amount and/or medication type can be altered, and the resultingeffect determined by another future wet run. For sedentary patients, wetrun solution application combined with a “chemical” stress test can beused to gage the effect of a medication regimen. The period betweencolor detector evaluations can be selected based on the medication, andthe amount of time typically required to see the full effect. For sometest treatments the second test might only be minutes or hours later. Inother cases it will be appropriate to wait for at least one day, aplurality of days, a week, or more. For example a patient may beadministered a wet run, and then started on one or more medications. Asecond wet run to determine cardiovascular improvement (if any) would beadministered at least one day, a plurality of days, at least seven days,1-10 days, or 5-15 days after the medication is started, and optionallyrepeated periodically on the same schedule.

Detecting Premature Ventricular Contractions

A premature ventricular contraction (PVC) is a cardiac event which maybe experienced as a “skipped beat” or palpitations in the chest. In anormal heartbeat, the ventricles contract after the atria havecontracted, which fills the ventricles. In a PVC, the ventriclescontract first, before the atria have filled the ventricles with blood.This makes the heart pumping activity less effective and reducescirculation efficiency. PVC may be a sign of low oxygenation in heartmuscle.

Heart electrical activity indicative of PVC can be detected by an EKG.However, PVC often only manifests sporadically. Thus, a patientsuffering from PVC who is only connected to an EKG for a relativelybrief period (e.g. during a visit to a doctor's office) may not have anydetectable events during that period.

PVCs reduce the heart's ability to generate sufficient blood flowthroughout the circulatory system. PVC rapidly affects the color of theskin. Specifically, it briefly but detectably decreases the red color ofthe skin (due to the presence of less red blood in capillaries) from thenormal or baseline red level. This drop in skin redness can be detectedby colorimetric means (such as a wet run) as an alternative method ofdiagnosing PVC without requiring an EKG machine. In particular, apatient can be fitted with a wearable color detector unit to monitorskin color for longer periods, such as for one or more days. This allowsmonitoring to continue for longer periods so that PVCs, if any, arelikely to be detected.

Emergency Room, Intensive Care, and Surgical Theater Monitoring

Color detector monitoring can be used to continuously monitor patientcardiovascular status during high-risk situations such as in anemergency room, ambulance, intensive care unit, catheter lab, or asurgical theater. The color detector is a useful addition to knownmedical monitoring devices such as blood pressure monitors, puleoximeter, EKG, heart rate monitors, and the like, providing additionaland confirmatory information in real-time. Color detectors' constant andimmediate feedback, unlike some alternative monitoring devices (such asa blood pressure cuff) which do not provide continuous data. In oneembodiment, color detector data, blood pressure, oxygenation, and heartrate are all collected and monitored simultaneously in a patient duringa surgical or other medical procedure. In some instances the colordetector will provide warnings about medical problems beforeconventional monitoring devices because the micro circulatoryenvironment (e.g. skin capillaries) exhibits detectable changes morequickly than the macro circulatory environment (which is correlated withconventional vital signs such as heart rate and blood pressure).

In particular, color detectors can be beneficially paired with heartrate monitors to help differentiate medical events which cause elevatedheart rates based on skin red shift. Wet run monitoring is preferred,and may advantageously be performed. Cardiac output can varyindependently of heart rate because of changes in stroke volume, forexample (cardiac output=stroke volume×heart rate).

A patient with severe internal bleeding has increased heart rate as thebody tries to compensate for dropping blood pressure due to blood loss.This is likely to be accompanied by a brief positive skin red shift (dueto increased heart pumping of blood to the capillaries), followed by asustained negative red shift (blood loss leads to less blood incapillaries).

A heart attack is characterized by increased heart rate as the heartstruggles to maintain blood flow. There will be little change in skinredness levels because the increased heart rate is not effective insustaining strong overall blood flow since portions of the heart muscleare oxygen-starved.

A patient experiencing fear or stress will exhibit both increased heartrate and positive skin red shift.

A fluctuating, up and down “sawtooth” red shift pattern is symptomaticof cardiac stress.

Consider, for example, a patient in a cardiac catheterization laboratorywho is exhibiting tachycardia (elevated heart rate). There are multiplepossible causes of tachycardia which require very different reactions bythe clinician. If the patient is suffering from stress, pain or anxietythey will have a positive red shift. Additional anesthesia may beindicated. If the patient is bleeding they will (at least eventually)have a negative red shift. Thus, physicians may evaluate the patient forpossible blood loss in response to a negative red shift.

Dry and (preferably) wet runs can also be used to detect improvedcirculation (i.e. positive red shift) in skin having capillaries whichare downstream of a vascular intervention. For example, monitoring redshift on skin which is downstream from a stenosis and/or an artery beingtreated with balloon angioplasty or stent manipulation. Objective andquantified evidence is therefore provided almost immediately regardingimprovements in tissue perfusion (if any) downstream of the subjectartery. Color detector skin monitoring can also be used to evaluateperfusion downstream of procedures (such as vein harvesting) which couldharm perfusion. Surgical methods, arrangements, and devices utilizingcolor detectors (including wet runs) for surgical purposes are alsowithin the scope of the invention.

Color detector perfusion monitoring methods and devices are contemplatedfor tourniquet application. For example, when performing lower extremitycompartmentalization for procedures such as hip replacement and kneereplacement. Sufficient compression is necessary to control blood flowand blood loss. Excess pressure, however, can cause tissue damage. Colordetector perfusion assessment downstream of the tourniquet can be usedto determine and confirm that tourniquet pressure is not excessive,based on the presence of a threshold minimum level of perfusion (e.g. asdetermined by degree of negative red shift vs. baseline). This isparticularly important when performing compartmentalization on a patienthaving peripheral artery disease or diabetes cholesterol arterialdisease, which negatively affect the micro circulation of the arterialcirculatory blood supply.

Color detector perfusion monitoring methods and devices are contemplatedas an alternative or supplement to known blood gas evaluation means. Forexample, to provide continuous monitoring of blood pH, oxygen, carbondioxide, hemoglobin, and bicarbonate levels. It is anticipated thatblood characteristics such as those above are capable of calculation andderivation based on color changes in the skin. Such methods and devicesare contemplated for use, for example, in continuously monitoringpatient for surgery or intensive care to track homeostasis. Colordetector data on one or more color traits could be fed to a deviceprogrammed to derive blood traits from the data. The derived bloodtraits and/or raw color detector data could in turn be displayed to anoperator. A color detector device could be strapped to the arm oranother accessible area with no hair or having hair removed. Thepatient's spectrophotometric colorimetric evaluation would continuouslybe input into a computer database that will monitor homeostasis and thebasal metabolic environment of the tissue. This will assist thephysician in adjusting medications, oxygenation, and other therapeuticinputs. It is contemplated that color detector monitoring will in somecases alert the physician to patient deterioration before otherphysiological parameters (e.g. blood pressure, heart rate) will.

Estimation of patient metabolic rates, including basal metabolic rates,in real time and derived from continuous color detector input, is alsocontemplated.

Diagnosis of arterial wall stretching during catheter procedures,hypertension, sepsis, blood loss, and hemorrhage based on skin colorchanges, including but not limited to red shift caused by changes incapillary blood perfusion, are also anticipated.

CPAP Machines and Obstructive Sleep Apnea

Color detector devices and methods are also relevant to diagnosing andtreating respiratory conditions such as sleep apnea. Sleep apnea is asleep disorder caused by pauses in breathing, or periods of shallowbreathing, during sleep. Obstructive sleep apnea is the most common typeof sleep apnea. Common symptoms include snoring, poor quality sleep, andtiredness during the daytime. Continuous positive airway pressure (CPAP)is a common treatment for severe obstructive sleep apnea.

Diagnostic tests for sleep apnea include home oximetry, orpolysomnography in a sleep clinic. Pulse oximetry is a noninvasivemethod for monitoring oxygen saturation. A typical (transmissive) pulseoximeter is a sensor device is placed on the fingertip or earlobe. Thedevice passes two different wavelengths of light through the body partto a photodetector. The light absorbed at the two wavelengths is used toderive blood oxygen levels. Pulse oximetry more specifically measureshemoglobin saturation. It does not monitor ventilation, and is not acomplete measure of respiratory efficiency.

Continuous positive airway pressure (CPAP) devices are positive airwaypressure ventilators. They are used to apply light, continuous airpressure to keep airways continuously open in people who are able tobreathe spontaneously on their own. CPAP is commonly used by people whohave breathing problems, such as sleep apnea. A common CPAP deviceincludes a plastic facial mask which is connected by a tube to a smallbedside CPAP machine. CPAP devices may also be used to treat prematureinfants whose lungs have not yet fully developed.

Color detector methods and devices can be used to monitor skinperfusion, and may, for example, be used to compliment oximeters. Forexample, monitoring skin red shift to identify reduced skin perfusionresulting from respiratory apnea or severe snoring. This information, incombination with additional data such as pulse oximetry, heart rate, andblood pressure, can be used to diagnose likely sleep apnea. Colordetector perfusion data can be used to determine when sufficient airflow is being provided to a sleep apnea patient by a CPAP machine byconfirming the absence of dips in perfusion (below baseline) caused byinterrupted breathing, even while the patient is asleep. Color detectordata can be used to calibrate CPAP treatments and machines. CPAPmachines and respiratory diagnostic arrangements including or linked toa color detector are contemplated. For example, a CPAP machine linked toa color detector which is calibrated using color detector data to use aconsistently effective air flow rate, and/or which continuously monitorspatient perfusion and uses the information to automatically vary airflow. Air flow can be raised in response to low perfusion, and reducedor maintained in light of adequate or high perfusion.

In one embodiment, a physician or technician sets initial parameters fora CPAP machine and treatment. During use, skin perfusion is measuredwhile the machine is in use (e.g. while sleeping), potentially incombination with monitoring other physiological information. The CPAPmachine increases, decreases, or maintains air flow and pressure tomaintain skin perfusion (derived from red shift) in a normal and desiredrange. In an alternative embodiment and method perfusion data (and otherdata) is recorded and stored during used (e.g. overnight). The data isused by the physician to analyze sleep quality, CPAP effectiveness,and/or to alter the CPAP treatment. The method and arrangement can beused to avoid inadequate and unnecessarily high (and uncomfortable) airflow during CPAP treatment.

Using an oximeter, once hemoglobin oxygen saturation has been reached,the measured oxygen level will remain at 100% regardless of how muchoxygen the tissue actually has and can use. Color detector monitoringprovides information on total perfusion, which importantly includesblood flow. This provides a better overall picture of that patient'srespiratory status and the adequacy of CPAP treatment.

Without limitation, CPAP machines and other respiratory assistancemachines which include a color detector for measuring skin perfusionbased on red shift, and which calibrate or adjust air flow on thatbasis, are therefore within the scope of this invention. Methods oftreating and diagnosing patients with respiratory conditions such assleep apnea using color detector perfusion data are also within thescope of the invention.

Wearable Color Detectors

Skin red shift reactions can be monitored and charted over time tomonitor the course of a patient's vascular health and/or theeffectiveness of medication.

Wearable color detectors can be used to monitor and record skin colorvariation (to gauge cardiovascular health and performance) over longerperiods and as they perform various activities outside of medicalfacilities. For example, monitoring for a plurality or hours, aplurality of days, or at least 1 hour, 5 hours, 24 hours, or 72 hours. Awatch-like device analogous to a Fitbit® which performs colorimetricmonitoring, for example, would be suited to this purpose. Units whichalso measure heart rate, distances traveled, steps, and the like couldalso be useful. Alternative designs could be mounted in any area of thebody such as the wrist, arm, leg, or back.

Color detector monitoring can be performed during an exercise routine(e.g. with a wearable color detector) to measure the degree and durationof vascular stimulation achieved, with greater red shift indicating morestimulation. Red shift data can be applied to determine cardiovascularexertion and performance before, during, and after exercise regimens.They can also be used to measure vascular response to a given exerciseregimen repeated over time, to monitor patient improvement over a periodof weeks or months. This information can in turn be used to optimizeexercise duration and levels for a particular individual.

Wearable color detectors preferably include mounting means forpositioning at least one input for receiving light against a patient'sskin for extended periods. For example, belts, wrist bands, straps,adhesives, wraps, plastic ties, or other means. Mounting means can bereversibly fixable to the patient using buckles, hook and loopfasteners, ties, an elastic band which stretches over a leg, arm, orhead, and the like.

Wearable color detectors may save color data locally, or may transmitcolor data for storage and processing at a separate location, such as byBluetooth, cellular, or other known methods.

Preferred wearable arrangements may incorporate both wet run chemicalsand one or more color detectors positioned adjacent the same area(s) ofthe wearer's skin (e.g. adjacent, or within 1 or 0.5 inches), andmethods using such wearable items. One embodiment is a garment includinga wet run color detector adjacent a wet run carrier holding wet runchemical, and a dry run color detector at a different location. In apreferred embodiment the color detectors are positioned in the garment(e.g. a shirt) near a user's back, upper back, or shoulder blades inmirror-image locations. The garment can be shaped and sized to hold thecolor detectors and carrier against the skin, and/or adhesives could beused to maintain the items against the skin.

Comparing Simultaneous Red Wet & Dry Run Red Levels

It has also been found that in healthy patients, when wet run and dryrun data are contemporaneously collected from a given patient over time(e.g. over the course of a single stress test), wet run red level isgenerally greater than dry run red level for a given patient. Forexample, maximum wet run red level (e.g. “a” in L/a/b scale) is at least5% or at least 10% greater than dry run at their respective maximums orpeaks, or at the wet run maximum peak. See illustrative FIG. 11.Conversely, in unhealthy patients, maximum wet run red level isgenerally equal to or less than dry run red levels. For example, dry runred level is equal to or greater than wet run red level, or is greaterthan wet run red level, at their respective peaks, or at wet run peak.See illustrative FIG. 12. Another useful yardstick is that in a healthypatient wet run redness will be greater than dry run redness over atleast 60%, at least 70%, or at least 80% of the time period or timepoints or the tests. Further, it can be indicative of poorcardiovascular health if dry run redness is equal to or greater than wetrun redness over at least 50%, at least 60%, or at least 70% of the timeperiod or time points of a stress test.

The wet and dry run measurements are preferably taken on two differentbut corresponding locations (e.g. both shoulder blades, both upper arms,opposite sides of lower back, etc.) using one or, preferably, two colordetectors. In a preferred approach both color detectors are strapped onor otherwise worn by the patient during an exercise regimen, althoughsimilar results can also be achieved otherwise, if less conveniently,such as by using a single color detector alternatingly on two wet anddry skin areas. Preferably the wet and dry run measurements are takenover a number of time points either simultaneously, or close in time(e.g. within 10 or 20 seconds).

FIG. 13 is a curve for normal patient P.T. where the wet run peak isabout 7% greater than the dry run peak.

FIG. 14 is a curve for normal patient D.V. having a wet run peak about22% higher than the dry run peak, and where the wet run redness levelremains above the dry run level over most of the stress test andrecovery phase.

FIG. 15 is a curve for patient C.P. where the dry run red peak is about22% higher than the wet run peak. The dry run redness is also above wetrun redness through most of the stress test. Subsequent to this test,patient C.P. was diagnosed as having ventricular tachycardia, a fastheart rate which arises from improper electrical activity in theventricles of the heart. Ventricular tachycardia may result in cardiacarrest and turn into ventricular fibrillation.

FIG. 16 is a curve for unhealthy patient C.V. In addition to having dryrun red levels which are greater than or equal to the wet run red levelsover most of the procedure and a higher dry run maximum, both the wetand dry curves have a jagged, sawtooth form which is indicative ofobstructive coronary disease.

The present invention includes methods, devices, and arrangements formeasuring and comparing contemporaneous wet run and dry run data from asingle patient over a period of time, e.g. over the course of a stresstest or other exercise regimen. In preferred embodiments two colordetectors are used, one each for wet and dry runs, each positioned oncorresponding but opposite skin areas (e.g. both shoulder blades,opposite sides of back, both upper arms, etc.). In preferredembodiments, both color detectors are wearable. Methods and deviceswhich display wet run and dry run data for a patient over time (e.g. aline graph or a chart) are useful for comparing the two data sets.

While a specific embodiment of the invention has been shown anddescribed in detail to illustrate the application of the principles ofthe invention, it will be understood that the invention may be embodiedotherwise without departing from such principles.

What is claimed is:
 1. A method for determining a red shift for apatient during a stress test, the method comprising: (A) applying a wetrun solution to a testing area of a skin surface of the patient, whereinthe wet run solution comprises acetylcholine; (B) positioning a colordetector on the patient after said application of wet run solution,wherein the color detector is configured for detecting at least a redwavelength of light and comprises an input for receiving light, andwherein the input is positioned to receive light from said testing area;(C) making and saving a baseline color measurement of the testing areausing the color detector, said baseline color measurement comprising abaseline skin redness level of the testing area with the patientresting; (D) initiating an exercise protocol after the baseline colormeasurement, wherein the exercise protocol comprises the patientengaging in a physical exercise; (E) making and saving a plurality ofexercise color measurements of the testing area at different timesduring the exercise protocol, said exercise color measurements eachcomprising skin redness levels measured by the color detector; (F)ending the exercise protocol by the patient ending the physicalexercise; (G) after the exercise protocol ends, beginning a recoveryphase, with the patient resting during the recovery phase; (H) makingand saving a plurality of recovery color measurements of the testingarea at different times during the recovery phase, said recovery colormeasurements each comprising skin redness levels; (I) calculating thered shift for the patient, the red shift being calculated by comparingthe baseline skin redness level and one of a maximum skin redness leveland a minimum skin redness level, said maximum skin redness level orminimum skin redness level being selected from the exercise colormeasurements and the recovery color measurements; and (J) diagnosing thepatient as having unsatisfactory cardiovascular health when a negativered shift value is calculated by comparing the baseline skin rednesslevel with the minimum skin redness level to determine that the negativered shift value has occurred.
 2. The method of claim 1, furthercomprising displaying on a display a graph plotting skin redness levelsover a period of time, said graph comprising the baseline colormeasurement, at least one exercise color measurement of said pluralityof exercise color measurements, and at least one recovery colormeasurement of said plurality of recovery color measurements.
 3. Themethod of claim 1, wherein said plurality of exercise color measurementsand said plurality of recovery color measurements are made at evenlyspaced time intervals, said time intervals being between 10 seconds andfive minutes; and wherein the exercise protocol comprises increasing atleast one of a speed and a resistance of the physical exercise one ormore times.
 4. The method of claim 1, wherein the color detector isselected from a colorimeter and a spectrophotometer.
 5. The method ofclaim 1, wherein the wet run solution further comprises at least one ofalcohol and water.
 6. The method of claim 1, wherein the wet runsolution further comprises at least one of petroleum jelly and an oil.7. The method of claim 1, wherein the exercise protocol comprises thepatient using at least one exercise machine selected from a treadmill, astationary bicycle, an elliptical trainer, and an arm ergometer.
 8. Amethod for determining a red shift for a patient during a stress test,the method comprising: (A) applying a wet run solution to a testing areaof a skin surface of the patient, wherein the wet run solution comprisesacetylcholine; (B) positioning a color detector on the patient aftersaid application of wet run solution, wherein the color detector isconfigured for detecting at least a red wavelength of light andcomprises an input for receiving light, and wherein the input ispositioned to receive light from said testing area; (C) making andsaving a baseline color measurement of the testing area using the colordetector, said baseline color measurement comprising a baseline skinredness level of the testing area with the patient resting; (D)initiating an exercise protocol after the baseline color measurement,wherein the exercise protocol comprises the patient engaging in aphysical exercise; (E) making and saving a plurality of exercise colormeasurements of the testing area at different times during the exerciseprotocol, said exercise color measurements each comprising skin rednesslevels measured by the color detector; (F) ending the exercise protocolby the patient ending the physical exercise; (G) after the exerciseprotocol ends, beginning a recovery phase, with the patient restingduring the recovery phase; (H) making and saving a plurality of recoverycolor measurements of the testing area at different times during therecovery phase, said recovery color measurements each comprising skinredness levels; (I) calculating the red shift for the patient, the redshift being calculated by comparing the baseline skin redness level andone of a maximum skin redness level and a minimum skin redness level,said maximum skin redness level or minimum skin redness level beingselected from the exercise color measurements and the recovery colormeasurements; and (J) diagnosing the patient as having satisfactorycardiovascular health when a positive red shift value of at least +10%is calculated by comparing the baseline skin redness level with themaximum skin redness level to determine that the positive red shiftvalue of at least +10% has occurred.
 9. The method of claim 8, furthercomprising displaying on a display a graph plotting skin redness levelsover a period of time, said graph comprising the baseline colormeasurement, at least one exercise color measurement of said pluralityof exercise color measurements, and at least one recovery colormeasurement of said plurality of recovery color measurements.
 10. Themethod of claim 8, wherein said plurality of exercise color measurementsand said plurality of recovery color measurements are made at evenlyspaced time intervals, said time intervals being between 10 seconds andfive minutes; and wherein the exercise protocol comprises increasing atleast one of a speed and a resistance of the physical exercise one ormore times.
 11. The method of claim 8, wherein the color detector isselected from a colorimeter and a spectrophotometer.
 12. The method ofclaim 8, wherein the wet run solution further comprises at least one ofalcohol and water.
 13. The method of claim 8, wherein the wet runsolution further comprises at least one of petroleum jelly and an oil.14. The method of claim 8, wherein the exercise protocol comprises thepatient using at least one exercise machine selected from a treadmill, astationary bicycle, an elliptical trainer, and an arm ergometer.